MY PATIENT HAS READ THAT HIS PPI S MAY BE TROUBLE. NOW WHAT? Clarence Wong MD FRCPC Associate Professor FACULTY/PRESENTER DISCLOSURE Faculty: Clarence Wong Relationships with commercial interests: Grants/Research Support: Alberta Innovates, Pendopharm Speakers Bureau/Honoraria: Ferring; Pendopharm; Allergan Consulting Fees: Olympus; Ferring; Allergan; Takeda Other: Employee of AHS, Univ of Alberta 1
OBJECTIVES After this session, the attendee will have a better understanding of: PPI Pharmacokinetics and Physiology How to compare PPIs PPI Risk - Real or False? Alternatives to PPI G A S T R I C A C I D S E C R E T I O N P H Y S I O L O G Y Used in practice since late 1980s Revolutionized treatment of gastric acid related disorders 2
ACID SUPPRESSION WITH PPIS PPIs absorbed in small bowel and secreted into gastric lumen as a prodrug pka = 4-5 (ph when 50% protonated) protonation on pump leads to disulfide bond and a positive charge holds drug on lumenal side 1000x concentration vs serum short t½ - 3-5 days to reach steady state PPI WHEN TO TAKE maximal effect if parietal cells & pumps active Fasting State: Only 5% pumps active Meals: 60-70% active Thus, administer ~30 minutes prior to meal Usually AM Metabolized by hepatic cytochrome P450 (CYP 2C19/3A4) 3
COMPARING PPIS PPI INDICATIONS Indicated to treat: Peptic Ulcer disease GI Bleeding GERD Erosive esophagitis and Barrett s esophagus NSAID associated ulcers Chemoprophylaxis Eradication of H. pylori Zollinger-Ellision Syndrome 4
PPI PHARMACOKINETICS UpToDate 2018 PPI EFFICACY-IS THERE A DIFFERENCE? Accessed on December 05, 2007 systematic review of 12 randomized trials examining the relative effectiveness of different PPI doses and dosing regimens found no consistent difference in symptom resolution and esophagitis healing rates 5
DEXLANSOPRAZOLE INCREASED AUC PPI PRICING 6
PPI RISK REAL OR FALSE? PPI SIDE EFFECTS Common Side Effects are Minor: Headache Diarrhea Constipation Abdominal Discomfort Long term? 7
POTENTIAL ADVERSE EFFECTS OF LONG TERM PPI SUPPRESSION In General: Observational Studies Association but not causality Observational Research Should have: RR > 2-3 (cohort) OR >3-4 (case control) EMJ Gastroenterol. 2016;5[1]:74-81 PPI & HIP FRACTURES Risk of fracture went from 3 in 10,000 to 9 in 10,000 in one year 8
meta-analysis encompassing 178,686 subjects no significant association between PPI therapy and bone mineral density Association, not causality No biologic plausibility No evidence of dose response or duration effect PPIS AND CAP Integrated Primary Care Information (IPCI) Netherlands 364,683 followed 5551 had pneumonia PPI use AOR 1.89 (H2RA 1.63) 9
CAG POSITION PAPER - CAP/PPI 60 studies in 13 years up to 2006 despite all the RCTs on PPI use only 7 mentioned respiratory infection N=2271 (4.3% PPI group; 4.9% PLAC) Laheji did not match the current and past users of acid suppressive medications with controls matched: 1 case of CAP in 100 yrs of ASD use PROTOPATHIC BIAS PPIs given in the early treatment of a disorder In this case, cough/chest discomfort (early pneumonia) given PPI UKGP Research Database: PPI 2 days OR 6.53 PPI 7 days OR 3.79 PPI 14 days OR 3.21 PPI Long term OR 1.02 Sarkar, 2008, Annals Int Med 149:391 10
PPIS AND CDAD Howell et al. 2010 Arch Int Med 170:784 Observational studies possible interaction No causality explained Mainly inpatients with multiple comorbidities CAG statement (2005): Possible interaction Review risk vs benefits of PPIs More selected for inpatients PPIS AND CDAD 11
ALTERNATIVES TO PPI THERAPY NO ALTERNATIVES Peptic Ulcer disease GI Bleeding GERD Erosive esophagitis and Barrett s esophagus NSAID associated ulcers Chemoprophylaxis Eradication of H. pylori Zollinger-Ellision Syndrome 12
ALTERNATIVES Change Anatomy Fundoplicaton Change Harmful Medications Reduce/Don t prescribe NSAIDs Change Reflux Weight Reduction Exercise Change Diet Don t eat close to supine/bedtime DOSE REDUCTION After use 3-5 days in a row Step Down therapy Avoid rebound gastric acid hypersecretion Reduce by 50% per week BID to daily; Daily to Q2D, Q2D to twice per week, Twice per week to QWeekly 13
SUMMARY In this session, we have reviewed: PPI Physiology and Pharmacokinetics PPI Indications & Comparisons PPI side effects and adverse effects Observational studies/weak Associations Alternative to PPIs 14